Artemisinin Derivatives
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Artemisinin () and its
semisynthetic Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with ...
derivatives are a group of
drugs A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via inhalation, injection, smoking, ingestio ...
used in the treatment of
malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...
due to ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''. It was discovered in 1972 by
Tu Youyou Tu Youyou ( zh, c=屠呦呦, p=Tú Yōuyōu; born 30 December 1930) is a Nobel Prize-winning Chinese malariologist and pharmaceutical chemist. She discovered artemisinin (also known as , ) and dihydroartemisinin, used to treat malaria, a brea ...
, who shared the 2015
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, acco ...
for her discovery.
Artemisinin-based combination therapies Antimalarial medications or simply antimalarials are a type of antiparasitic chemical agent, often naturally derived, that can be used to treat or to prevent malaria, in the latter case, most often aiming at two susceptible target groups, young c ...
(ACTs) are now standard treatment worldwide for ''P. falciparum'' malaria as well as malaria due to other species of ''
Plasmodium ''Plasmodium'' is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of ''Plasmodium'' species involve development in a Hematophagy, blood-feeding insect host (biology), host which then inj ...
''. Artemisinin can be extracted from the herb ''
Artemisia annua ''Artemisia annua'', also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood, is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North Ameri ...
'' (sweet wormwood), which is used in
traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medicine, alternative medical practice drawn from traditional medicine in China. A large share of its claims are pseudoscientific, with the majority of treatments having no robust evidence ...
. Alternatively, it can be prepared by a
semi-synthetic Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds wit ...
method from a precursor compound that can be produced using a
genetically engineered Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including th ...
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
, which is much more efficient than extraction from the plant. Artemisinin and its derivatives are all
sesquiterpene lactone Sesquiterpene lactones (SLs) are a class of sesquiterpenoids that contain a lactone ring. They are most often found in plants of the family Asteraceae (daisies, asters). Other plant families with SLs are Umbelliferae (celery, parsley, carrots) ...
s containing an unusual
peroxide In chemistry, peroxides are a group of Chemical compound, compounds with the structure , where the R's represent a radical (a portion of a complete molecule; not necessarily a free radical) and O's are single oxygen atoms. Oxygen atoms are joined ...
bridge. This endoperoxide 1,2,4-trioxane ring is responsible for their antimalarial properties. Few other natural compounds with such a peroxide bridge are known. Artemisinin and its derivatives have been used for the treatment of malarial and parasitic worm (helminth) infections. Advantages of such treatments over other anti-parasitics include faster parasite elimination and broader efficacy across the parasite life-cycle; disadvantages include their low
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
, poor
pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...
properties, and high cost. Moreover, use of the drug by itself as a monotherapy is explicitly discouraged by the
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
, as there have been signs that malarial parasites are developing resistance to the drug. Combination therapies, featuring artemisinin or its derivatives alongside some other antimalarial drug, constitute the contemporary standard-of-care treatment regimen for malaria.


Medical use

The
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
(WHO) recommends artemisinin or one of its derivatives ― typically in combination with a longer-lasting
partner drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...
― as frontline therapy for all cases of malaria. For
uncomplicated malaria Malaria is a mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes symptoms that typically include fever, fatigue, vomiting, and headaches. In severe cases, it can cause jaundice, seiz ...
, the WHO recommends three days of oral treatment with any of five artemisinin-based combination therapies (ACTs):
artemether/lumefantrine Artemether/lumefantrine, sold under the trade name Coartem among others, is a combination of the two medications artemether and lumefantrine. It is used to treat malaria caused by ''Plasmodium falciparum'' that is not treatable with chloroquine ...
,
artesunate/amodiaquine Artesunate/amodiaquine, sold under the trade name Camoquin among others, is a medication used for the treatment of malaria. It is a fixed-dose combination of artesunate and amodiaquine. Specifically it recommended for acute uncomplicated ''Plas ...
(ASAQ), artesunate/mefloquine, dihydroartemisinin/piperaquine, or artesunate/sulfadoxine/pyrimethamine. In each of these combinations, the artemisinin derivative rapidly kills the parasites, but is itself rapidly cleared from the body. The longer-lived partner drug kills the remaining parasites and provides some lingering protection from reinfection. For severe malaria, the WHO recommends
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
or
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
treatment with the artemisinin derivative
artesunate Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of ...
for at least 24 hours. Artesunate treatment is continued until the treated person is well enough to take oral medication. They are then given a three-day course of an ACT, for uncomplicated malaria. Where artesunate is not available, the WHO recommends intramuscular injection of the less potent artemisinin derivative
artemether Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also ...
. For children less than six years old, if injected artesunate is not available the WHO recommends
rectal administration Rectal administration (colloquially known as boofing or plugging) uses the rectum as a route of administration for medication and other fluids, which are absorbed by the rectum's blood vessels,The rectum has numerous blood vessels available to a ...
of artesunate, followed by referral to a facility with the resources for further care. Artemisinins are not used for malaria prevention because of the extremely short activity (
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
) of the drug. To be effective, it would have to be administered multiple times each day.


Contraindications

The WHO recommends avoiding ACT for women in their first trimester of pregnancy due to a lack of research on artemisinin's safety in early pregnancy. Instead the WHO recommends a seven-day course of
clindamycin Clindamycin is a lincosamide antibiotic medication used for the treatment of a number of bacterial infections, including osteomyelitis (bone) or joint infections, pelvic inflammatory disease, strep throat, pneumonia, acute otitis media (mi ...
and
quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to ''Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal leg ...
. For pregnant women in their second or third trimesters, the WHO recommends a normal treatment course with an ACT. For some other groups, certain ACTs are avoided due to side effects of the partner drug: sulfadoxine-pyrimethamine is avoided during the first few weeks of life as it interferes with the action of
bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...
and can worsen
neonatal jaundice Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral ...
. In
HIV-positive The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
people, the combination of
trimethoprim/sulfamethoxazole Trimethoprim/sulfamethoxazole, sold under the trade names Bactrim, Cotrim (a short form of the British Approved Name, Co-trimoxazole) and Septra, among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacte ...
,
zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mothe ...
-containing
antiretroviral The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mu ...
treatments, and
ASAQ Artesunate/amodiaquine, sold under the trade name Camoquin among others, is a medication used for the treatment of malaria. It is a fixed-dose combination of artesunate and amodiaquine. Specifically it recommended for acute uncomplicated ''Plasmo ...
is associated with
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
. The combination of the HIV drug
efavirenz Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlesti ...
and ASAQ is associated with liver toxicity.


Adverse effects

Artemisinins are generally well tolerated at the doses used to treat malaria. The side effects from the artemisinin class of medications are similar to the symptoms of malaria:
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
,
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
,
loss of appetite Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...
, and
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
. Mild blood abnormalities have also been noted. A rare but serious adverse effect is
allergic reaction Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
. One case of significant liver inflammation has been reported in association with prolonged use of a relatively high-dose of artemisinin for an unclear reason (the patient did not have malaria). The drugs used in combination therapies can contribute to the adverse effects experienced by those undergoing treatment. Adverse effects in patients with acute ''P. falciparum'' malaria treated with artemisinin derivatives tend to be higher.


Chemistry

An unusual component of the artemisinin molecules is an endoperoxide 1,2,4-trioxane ring. This is the main antimalarial centre of the molecule. Modifications at carbon 10 (C10) position give rise to a variety of derivatives which are more powerful than the original compound. Because the physical properties of artemisinin itself, such as poor bioavailability, limit its effectiveness, semisynthetic
derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
s of artemisinin have been developed. Derivatives of
dihydroartemisinin Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also availabl ...
were made since 1976.
Artesunate Artesunate (AS) is a medication used to treat malaria. The intravenous form is preferred to quinine for severe malaria. Often it is used as part of combination therapy, such as artesunate plus mefloquine. It is not used for the prevention of ...
,
arteether Artemotil (INN; also known as β-arteether), is a fast acting blood schizonticide specifically indicated for the treatment of chloroquine-resistant ''Plasmodium falciparum'' malaria and cerebral malaria cases. It is a semi-synthetic derivative ...
, and
artemether Artemether is a medication used for the treatment of malaria. The injectable form is specifically used for severe malaria rather than quinine. In adults, it may not be as effective as artesunate. It is given by injection in a muscle. It is also ...
were first synthesized in 1986. Many derivatives have been produced of which artelinic acid, artemotil, artemisone, SM735, SM905, SM933, SM934, and SM1044 are among the most powerful compounds. There are also simplified analogs in
preclinical development In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...
. Over 120 other derivatives have been prepared, but clinical testing has not been possible due to lack of financial support. Artemisinin is poorly soluble in oils and water. Therefore, it is typically administered via the digestive tract, either by oral or rectal administration. Artesunate however can be administered via the intravenous and intramuscular, as well as the oral and rectal routes. A synthetic compound with a similar trioxolane structure (a ring containing three oxygen atoms) named RBx-11160 showed promise in ''in vitro'' testing. Phase II testing in patients with malaria was not as successful as hoped, but the manufacturer decided to start Phase III testing anyway.


Mechanism of action

As of 2018, the exact mechanism of action of artemisinins has not been fully elucidated. Artemisinin itself is a
prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
of the biologically active
dihydroartemisinin Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also availabl ...
. This
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
undergoes cleavage of its
endoperoxide In organic chemistry, organic peroxides are organic compounds containing the peroxide functional group (). If the R′ is hydrogen, the compounds are called hydroperoxides, which are discussed in that article. The O−O bond of peroxides easily b ...
ring inside the
erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...
s. As the drug molecules come in contact with the
haem Heme (American English), or haem (Commonwealth English, both pronounced / hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a ligand of various proteins, more notably as a component of hemoglobin, which is necessary to b ...
(associated with the
hemoglobin Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
of the red blood cells), the
iron(II) oxide Iron(II) oxide or ferrous oxide is the inorganic compound with the formula FeO. Its mineral form is known as wüstite. One of several iron oxides, it is a black-colored powder that is sometimes confused with rust, the latter of which consists ...
breaks the endoperoxide ring. This process produces
free radicals In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired electron, unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemical reaction, chemi ...
that in turn damage susceptible proteins, resulting in the death of the parasite. In 2016 artemisinin was shown to bind to a large number of targets suggesting that it acts in a promiscuous manner. Artemisinin's endoperoxide moiety is however less sensitive to free iron(II) oxide, and therefore more active in the intraerythrocytic stages of ''P. falciparum''. In contrast, clinical practice shows that unlike other antimalarials, artemisinin is active during all life cycle stages of the parasite.


Resistance

Clinical evidence for artemisinin
drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...
in southeast Asia was first reported in 2008, and was subsequently confirmed by a detailed study from western
Cambodia Cambodia, officially the Kingdom of Cambodia, is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. It is bordered by Thailand to the northwest, Laos to the north, and Vietnam to the east, and has a coastline ...
. Resistance in neighbouring
Thailand Thailand, officially the Kingdom of Thailand and historically known as Siam (the official name until 1939), is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. With a population of almost 66 million, it spa ...
was reported in 2012, and in northern Cambodia,
Vietnam Vietnam, officially the Socialist Republic of Vietnam (SRV), is a country at the eastern edge of mainland Southeast Asia, with an area of about and a population of over 100 million, making it the world's List of countries and depende ...
and eastern
Myanmar Myanmar, officially the Republic of the Union of Myanmar; and also referred to as Burma (the official English name until 1989), is a country in northwest Southeast Asia. It is the largest country by area in Mainland Southeast Asia and has ...
in 2014. Emerging resistance was reported in southern
Laos Laos, officially the Lao People's Democratic Republic (LPDR), is the only landlocked country in Southeast Asia. It is bordered by Myanmar and China to the northwest, Vietnam to the east, Cambodia to the southeast, and Thailand to the west and ...
, central Myanmar and northeastern Cambodia in 2014. The parasite's kelch gene on chromosome 13 appears to be a reliable molecular marker for clinical resistance in Southeast Asia. In 2011, the WHO stated that resistance to the most effective antimalarial drug, artemisinin, could unravel national Indian malaria control programs, which have achieved significant progress in the last decade. WHO advocates the rational use of antimalarial drugs and acknowledges the crucial role of community health workers in reducing malaria in the region. Artemisinins can be used alone, but this leads to a high rate of return of parasites and other drugs are required to clear the body of all parasites and prevent a recurrence. The WHO is pressuring manufacturers to stop making the uncompounded drug available to the medical community at large, aware of the catastrophe that would result if the malaria parasite developed resistance to artemisinins. Two main mechanisms of resistance drive ''Plasmodium'' resistance to antimalarial drugs. The first one is an efflux of the drug away from its action site due to mutations in different transporter genes (like ''pfcrt'' in
chloroquine Chloroquine is an antiparasitic medication that treats malaria. It works by increasing the levels of heme in the blood, a substance toxic to the malarial parasite. This kills the parasite and stops the infection from spreading. Certain types ...
resistance) or an increased number of the gene copies (like pfmdr1 copy number in
mefloquine Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It ...
resistance). The second is a change in the parasite target due to mutations in corresponding genes (like, at the cytosol level, ''dhfr'' and ''dhps'' in
sulfadoxine Sulfadoxine (also spelled sulphadoxine) is an ultra-long-lasting sulfonamide used in combination with pyrimethamine to treat malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''A ...
-
pyrimethamine Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic disea ...
resistance or, at the mitochondrion level, ''
cytochrome b Cytochrome b is a protein found in the membranes of aerobic cells. In eukaryotic mitochondria (inner membrane) and in aerobic prokaryotes, cytochrome b is a component of respiratory chain complex III () — also known as the bc1 complex or ubiq ...
'' in
atovaquone Atovaquone, sold under the brand name Mepron, is an antimicrobial medication for the prevention and treatment of ''Pneumocystis jirovecii'' pneumonia (PCP). Atovaquone is a chemical compound that belongs to the class of naphthoquinones. Atova ...
resistance). Resistance of ''P. falciparum'' to the new artemisinin compounds involves a novel mechanism corresponding to a quiescence phenomenon.


Synthesis


Biosynthesis in ''Artemisia annua''

The biosynthesis of artemisinin is believed to involve the
mevalonate pathway The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...
(MVA) and the cyclization of
farnesyl diphosphate Farnesyl pyrophosphate (FPP), also known as farnesyl diphosphate (FDP), is the precursor to all sesquiterpenes, which comprises thousands of compounds. These include all sesquiterpenes as well as sterols and carotenoids. It is also used in the syn ...
(FDP). It is not clear whether the
non-mevalonate pathway The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-''C''-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the iso ...
can also contribute 5-carbon precursors (
IPP IPP may refer to: Organisations * Independent power producer * India Pride Project, recovering stolen Indian artefacts * Istituto per la Protezione delle Piante (Institute of Plant Protection), Italy * Max-Planck-Institut für Plasmaphysik, a ...
or
DMAPP Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...
), as occurs in other sesquiterpene biosynthetic systems. The routes from artemisinic alcohol to artemisinin remain controversial, and they differ mainly in when the reduction step takes place. Both routes suggested dihydroartemisinic acid as the final precursor to artemisinin. Dihydroartemisinic acid then undergoes photo-oxidation to produce dihydroartemisinic acid hydroperoxide. Ring expansion by the cleavage of hydroperoxide and a second oxygen-mediated hydroperoxidation finish the biosynthesis of artemisinin.


Chemical synthesis

The total synthesis of artemisinin has been performed from available organic starting materials, using basic organic reagents, many times. The first two total syntheses were a
stereoselective synthesis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...
by Schmid and Hofheinz at
Hoffmann-La Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...
in Basel starting from (−)- isopulegol (13 steps, ~5% overall yield), and a concurrent synthesis by Zhou and coworkers at the Shanghai Institute of Organic Chemistry from (''R'')-(+)-
citronellal Citronellal or rhodinal ( C10 H18 O) is a monoterpenoid aldehyde, the main component in the mixture of terpenoid chemical compounds that give citronella oil its distinctive lemon scent. Citronellal is a main isolate in distilled oils from the ...
(20 steps, ~0.3% overall yield). Key steps of the Schmid–Hofheinz approach included an initial Ohrloff stereoselective hydroboration/oxidation to establish the "off-ring" methyl stereocenter on the propene side chain; two sequential lithium-reagent mediated alkylations that introduced all needed carbon atoms and that were, together highly diastereoselective; and further reduction, oxidation, and desilylation steps performed on this mono-carbocyclic intermediate, including a final
singlet oxygen Singlet oxygen, systematically named dioxygen(singlet) and dioxidene, is a gaseous inorganic chemistry, inorganic chemical with the formula O=O (also written as or ), which is in a quantum state where all electrons are Radical (chemistry), spin p ...
-utilizing
photooxygenation A photooxygenation is a light-induced oxidation reaction in which molecular oxygen is incorporated into the product(s). Initial research interest in photooxygenation reactions arose from Oscar Raab's observations in 1900 that the combination of li ...
and
ene reaction In organic chemistry, the ene reaction (also known as the Alder-ene reaction by its discoverer Kurt Alder in 1943) is a chemical reaction between an alkene with an allylic hydrogen (the ene) and a compound containing a multiple bond (the enophile) ...
, which, after acidic workup closed the three remaining oxacyclic rings of the desired product, artemisinin, in a single step. (In essence, the final oxidative ring-closing operation in these syntheses accomplishes the closing three biosynthetic steps shown above.) A wide variety of further routes continue to be explored, from early days until today, including total synthesis routes from (''R'')-(+)-pulegone, isomenthene, and even 2-cyclohexen-1-one, as well as routes better described as partial or semisyntheses from a more plentiful biosynthetic precursor, artemisinic acid—in the latter case, including some very short and very high yielding
biomimetic synthesis Biomimetic synthesis is an area of organic chemical synthesis that is specifically biologically inspired. The term encompasses both the testing of a "biogenetic hypothesis" (''conjectured'' course of a biosynthesis in nature) through execution of ...
examples (of Roth and Acton, and Haynes et al., 3 steps, 30% yield), which again feature the singlet oxygen ene chemistry.


Synthesis in engineered organisms

The partnership to develop semisynthetic artemisinin was led by PATH's Drug Development program (through an affiliation with OneWorld Health), with funding from the
Bill & Melinda Gates Foundation The Gates Foundation is an American private foundation founded by Bill Gates and Melinda French Gates. Based in Seattle, Washington, it was launched in 2000 and is reported to be the third largest charitable foundation in the world, holding $ ...
. The project began in 2004, and initial project partners included the
University of California, Berkeley The University of California, Berkeley (UC Berkeley, Berkeley, Cal, or California), is a Public university, public Land-grant university, land-grant research university in Berkeley, California, United States. Founded in 1868 and named after t ...
(which provided the technology on which the project was based – a process that genetically altered yeast to produce artemisinic acid) and Amyris (a biotechnology firm in California, which refined the process to enable large-scale production and developed scalable processes for transfer to an industrial partner). In 2006, a team from UC Berkeley reported they had engineered ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'' yeast to produce a small amount of the precursor artemisinic acid. The synthesized artemisinic acid can then be transported out, purified and chemically converted into artemisinin that they claim will cost roughly US$0.25 per dose. In this effort of
synthetic biology Synthetic biology (SynBio) is a multidisciplinary field of science that focuses on living systems and organisms. It applies engineering principles to develop new biological parts, devices, and systems or to redesign existing systems found in nat ...
, a modified mevalonate pathway was used, and the yeast cells were engineered to express the enzyme amorphadiene synthase and a
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
monooxygenase Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation of ...
(CYP71AV1), both from ''
Artemisia annua ''Artemisia annua'', also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood, is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North Ameri ...
''. A three-step oxidation of
amorpha-4,11-diene Amorpha-4,11-diene is a precursor to artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to ''Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the ...
gives the resulting artemisinic acid. The UC Berkeley method was augmented using technology from various other organizations. The final successful technology is based on inventions licensed from UC Berkeley and the National Research Council (NRC) Plant Biotechnology Institute of Canada. Commercial production of semisynthetic artemisinin is now underway at
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
's site in Garessio, Italy. This second source of artemisinin is poised to enable a more stable flow of key antimalarial treatments to those who need them most. The production goal is set at 35 tonnes for 2013. It is expected to increase to 50–60 tons per year in 2014, supplying approximately one-third of the global annual need for artemisinin. In 2013, WHO's Prequalification of Medicines Programme announced the acceptability of semisynthetic artemisinin for use in the manufacture of active pharmaceutical ingredients submitted to WHO for prequalification, or that have already been qualified by WHO. Sanofi's active pharmaceutical ingredient (API) produced from semisynthetic artemisinin (artesunate) was also prequalified by WHO on May 8, 2013, making it the first semisynthetic artemisinin derivative prequalified. In 2010, a team from
Wageningen University and Research Wageningen University & Research (also known as WUR) is a public university, public research university in Wageningen, Netherlands, specializing in life sciences with a focus on agriculture, technical and engineering subjects. It is a globally i ...
reported they had engineered a close relative of tobacco, ''
Nicotiana benthamiana ''Nicotiana benthamiana'', colloquially known as benth or benthi, is a species of ''Nicotiana'' indigenous to Australia. It is a close relative of tobacco. A synonym for this species is ''Nicotiana suaveolens'' var. ''cordifolia'', a descripti ...
'', that can also produce the precursor, artemisinic acid.


Production and price

China and Vietnam provide 70% and East Africa 20% of the raw plant material. Seedlings are grown in nurseries and then transplanted into fields. It takes about 8 months for them to reach full size. The plants are harvested, the leaves are dried and sent to facilities where the artemisinin is extracted using a solvent, typically
hexane Hexane () or ''n''-hexane is an organic compound, a straight-chain alkane with six carbon atoms and the molecular formula C6H14. Hexane is a colorless liquid, odorless when pure, and with a boiling point of approximately . It is widely used as ...
. Alternative extraction methods have been proposed. The market price for artemisinin has fluctuated widely, between
US$ The United States dollar (Currency symbol, symbol: Dollar sign, $; ISO 4217, currency code: USD) is the official currency of the United States and International use of the U.S. dollar, several other countries. The Coinage Act of 1792 introdu ...
120 and $1,200 per kilogram from 2005 to 2008. The Chinese company Artepharm created a combination artemisinin and
piperaquine Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement ...
drug marketed as Artequick. In addition to
clinical research Clinical research is a branch of medical research that involves people and aims to determine the effectiveness (efficacy) and safety of medications, devices, diagnostic products, and treatment regimens intended for improving human health. The ...
performed in China and southeast Asia, Artequick was used in large-scale malaria eradication efforts in the
Comoros The Comoros, officially the Union of the Comoros, is an archipelagic country made up of three islands in Southeastern Africa, located at the northern end of the Mozambique Channel in the Indian Ocean. Its capital and largest city is Moroni, ...
. Those efforts, conducted in 2007, 2012, and 2013–14, produced a 95–97% reduction in the number of malaria cases in the Comoros. After negotiation with the WHO,
Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...
and Sanofi provide ACT drugs at cost on a nonprofit basis; however, these drugs are still more expensive than other malaria treatments. Artesunate injection for severe malaria treatment is made by the Guilin Pharmaceutical factory in China where production has received WHO prequalification. High-yield varieties of ''Artemisia'' are being produced by the Centre for Novel Agricultural Products at the
University of York The University of York (abbreviated as or ''York'' for Post-nominal letters, post-nominals) is a public Collegiate university, collegiate research university in York, England. Established in 1963, the university has expanded to more than thir ...
using molecular breeding techniques. Using seed supplied by Action for Natural Medicine (ANAMED), the
World Agroforestry Centre World Agroforestry (a brand name used by the International Centre for Research in Agroforestry, ICRAF) is an international institute headquartered in Nairobi, Kenya, and founded in 1978 as "International Council for Research in Agroforestry". ...
(ICRAF) has developed a hybrid, dubbed A3, which can grow to a height of 3 meters and produce 20 times more artemisinin than wild varieties. In northwestern
Mozambique Mozambique, officially the Republic of Mozambique, is a country located in Southeast Africa bordered by the Indian Ocean to the east, Tanzania to the north, Malawi and Zambia to the northwest, Zimbabwe to the west, and Eswatini and South Afr ...
, ICRAF is working together with a medical organization,
Médecins Sans Frontières (MSF; pronounced ), known in some English-speaking settings as Doctors Without Borders, is a charity that provides humanitarian medical care. It is a non-governmental organisation (NGO) of French origin known for its projects in conflict zo ...
, ANAMED and the Ministry of Agriculture and Rural Development to train farmers on how to grow the shrub from cuttings, and to harvest and dry the leaves to make artemisia tea. However, the WHO does not recommend the use of ''A. annua'' plant materials, including tea, for the prevention and treatment of malaria. In 2013, Sanofi announced the launch of a production facility in Garessio, Italy, to manufacture the antiplasmodial drug on a large scale. The partnership to create a new pharmaceutical manufacturing process was led by PATH's Drug Development program (through an affiliation with OneWorld Health), with funding from the Bill & Melinda Gates Foundation and based on a modified biosynthetic process for artemisinic acid, initially designed by
Jay Keasling Jay D. Keasling is a professor of chemical engineering and bioengineering at the University of California, Berkeley. He is also associate laboratory director for biosciences at the Lawrence Berkeley National Laboratory and chief executive officer ...
at UC Berkeley and optimized by
Amyris ''Amyris'' is a genus of flowering plants in the citrus family, Rutaceae. The generic name is derived from the Greek word αμ ('), which means "intensely scented" and refers to the strong odor of the resin. Members of the genus are commonly kno ...
. The reaction is followed by a
photochemical Photochemistry is the branch of chemistry concerned with the chemical effects of light. Generally, this term is used to describe a chemical reaction caused by absorption of ultraviolet (wavelength from 100 to 400  nm), visible (400–750&nb ...
process creating singlet oxygen to obtain the end product. Sanofi expects to produce 25 tons of artemisinin in 2013, ramping up the production to 55–60 tonnes in 2014. The price per kilogram will be US$350–400, roughly the same as the botanical source. Despite concerns that this equivalent source would lead to the demise of companies, which produce this substance conventionally through extraction of ''A. annua'' biomass, an increased supply of this drug will likely produce lower prices and therefore increase the availability for ACT treatment. In 2014, Sanofi announced the release of the first batch of semisynthetic artemisinin. 1.7 million doses of Sanofi's
ASAQ Artesunate/amodiaquine, sold under the trade name Camoquin among others, is a medication used for the treatment of malaria. It is a fixed-dose combination of artesunate and amodiaquine. Specifically it recommended for acute uncomplicated ''Plasmo ...
, a fixed-dose artemisinin-based combination therapy will be shipped to half a dozen African countries over the next few months. A 2016 systematic review of four studies from East Africa concluded that subsidizing ACT in the private retail sector in combination with training and marketing has led to the increased availability of ACT in stores, increased use of ACT for febrile children under five years of age, and decrease in the use of older, less effective antimalarials among children under five years of age. The underlying studies did not determine if the children had malaria nor determine if there were health benefits.


Metabolism

After ingestion or injection, artemisinin and its derivatives (arteether, artemether, and artesunate) are all rapidly converted in the bloodstream to
dihydroartemisinin Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA) is a drug used to treat malaria. Dihydroartemisinin is the active metabolite of all artemisinin compounds (artemisinin, artesunate, artemether, etc.) and is also availabl ...
(DHA), which has 5–10 times greater antimalarial potency than artemisinin. DHA is eventually converted in the liver into metabolites such as deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydrodeoxyartemisinin. These reactions are catalyzed by the enzymes
CYP2A6 Cytochrome P450 2A6 (abbreviated CYP2A6) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine an ...
,
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, and
CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...
, which belong to the
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
group present in the
smooth endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little ne ...
. These metabolites lack antimalarial properties due to the loss of the endoperoxide group (deoxyartemisinin however has anti-inflammatory and antiulcer properties.) All these metabolites undergo
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...
, after which they are excreted through the urine or feces.
Glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UDPGT or UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecu ...
s, in particular
UGT1A9 UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the ''UGT1A9'' gene. Function This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, suc ...
and
UGT2B7 UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltran ...
, are responsible for this process. DHA is also removed through
bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...
as minor
glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...
s. Due to their rapid metabolism, artemisinin and its derivatives are relatively safe drugs with a relatively high
therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...
.


History


Etymology

Artemisinin is an antimalarial lactone derived from ''qinghao'' (, ''
Artemisia annua ''Artemisia annua'', also known as sweet wormwood, sweet annie, sweet sagewort, annual mugwort or annual wormwood, is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North Ameri ...
'' or sweet wormwood). In 1596,
Li Shizhen Li Shizhen (July 3, 1518  – 1593), courtesy name Dongbi, was a Chinese acupuncturist, herbalist, naturalist, pharmacologist, physician, and writer of the Ming dynasty. He is the author of a 27-year work, the '' Compendium of Materia ...
recommended tea made from ''qinghao'' specifically to treat malaria symptoms in his ''
Compendium of Materia Medica The ''Bencao gangmu'', known in English as the ''Compendium of Materia Medica'' or ''Great Pharmacopoeia'', is an encyclopedic gathering of medicine, natural history, and Chinese herbology compiled and edited by Li Shizhen and published in th ...
''. The genus name is derived from the Greek goddess
Artemis In ancient Greek religion and Greek mythology, mythology, Artemis (; ) is the goddess of the hunting, hunt, the wilderness, wild animals, transitions, nature, vegetation, childbirth, Kourotrophos, care of children, and chastity. In later tim ...
and, more specifically, may have been named after Queen
Artemisia II of Caria Artemisia II of Caria ( Greek: Ἀρτεμισία; died 351 BC) was a naval strategist, commander and the sister (and later spouse) and the successor of Mausolus, ruler of Caria. Mausolus was a satrap of the Achaemenid Empire, yet enjoyed the ...
, a botanist and medical researcher in the fourth century BC.


Discovery

''Artemisia annua'' a common
herb Herbs are a widely distributed and widespread group of plants, excluding vegetables, with savory or aromatic properties that are used for flavoring and garnishing food, for medicinal purposes, or for fragrances. Culinary use typically distingu ...
found in many parts of the world. In 1967, a plant screening research program, under a secret military program code-named "
Project 523 Project 523 () is a code name for a 1967 secret military project of the People's Republic of China to find antimalarial medications. Named after the date the project launched, 23 May, it addressed malaria, an important threat in the Vietnam War. At ...
", was set up by the
People's Liberation Army The People's Liberation Army (PLA) is the military of the Chinese Communist Party (CCP) and the People's Republic of China (PRC). It consists of four Military branch, services—People's Liberation Army Ground Force, Ground Force, People's ...
to find an adequate treatment for malaria; the program and early clinical work were ordered by
Mao Zedong Mao Zedong pronounced ; traditionally Romanization of Chinese, romanised as Mao Tse-tung. (26December 18939September 1976) was a Chinese politician, revolutionary, and political theorist who founded the People's Republic of China (PRC) in ...
at the request of
North Vietnam North Vietnam, officially the Democratic Republic of Vietnam (DRV; ; VNDCCH), was a country in Southeast Asia from 1945 to 1976, with sovereignty fully recognized in 1954 Geneva Conference, 1954. A member of the communist Eastern Bloc, it o ...
ese leaders to provide assistance for their malaria-ridden army. In the course of this research in 1972,
Tu Youyou Tu Youyou ( zh, c=屠呦呦, p=Tú Yōuyōu; born 30 December 1930) is a Nobel Prize-winning Chinese malariologist and pharmaceutical chemist. She discovered artemisinin (also known as , ) and dihydroartemisinin, used to treat malaria, a brea ...
discovered artemisinin in the leaves of ''Artemisia annua''. Named ''qinghaosu'' (), it was one of many candidates tested as possible treatments for malaria by Chinese scientists, from a list of nearly 2,000
traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medicine, alternative medical practice drawn from traditional medicine in China. A large share of its claims are pseudoscientific, with the majority of treatments having no robust evidence ...
s. Tu Youyou also discovered that a low-temperature extraction process could be used to isolate an effective antimalarial substance from the plant. Tu says she was influenced by a traditional Chinese herbal medicine source ''The Handbook of Prescriptions for Emergency Treatments'' written in 340 CE by
Ge Hong Ge Hong (; b. 283 – d. 343 or 364), courtesy name Zhichuan (稚川), was a Chinese linguist, philosopher, physician, politician, and writer during the Eastern Jin dynasty. He was the author of '' Essays on Chinese Characters'', the '' Baopu ...
saying that this herb should be steeped in cold water. This book contained the useful reference to the herb: "A handful of ''qinghao'' immersed with two litres of water, wring out the juice and drink it all." Tu's team subsequently isolated an
extract An extract (essence) is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol, oil or water. Extracts may be sold as tinctures or absolutes or dried and powdered. The aromatic principles of ma ...
. Results were published in the ''
Chinese Medical Journal The ''Chinese Medical Journal'' is an official publication of the Chinese Medical Association, co-published by Chinese Medical Association Publishing House and Wolters Kluwer Medknow. The journal publishes peer-reviewed English-language articles, ...
'' in 1979. The extracted substance, once subject to purification, proved to be a useful starting point to obtain purified artemisinin. A 2012 review reported that artemisinin-based therapies were the most effective drugs for treatment of malaria at that time; it was also reported to clear malaria parasites from patients' bodies faster than other drugs. In addition to artemisinin, Project 523 developed a number of products that can be used in combination with artemisinin, including
lumefantrine Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination. Lumefantrine has a much longer half-life compared to artemether (3- ...
,
piperaquine Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement ...
, and
pyronaridine Pyronaridine is an antimalarial drug. It was first made in 1970 and has been in clinical use in China since the 1980s. In a small (n=88) malaria study in Camaroon, pyronaridine had a 100% cure rate, compared with 60% for chloroquine Chl ...
. In the late 1990s, Novartis filed a new Chinese patent for a combination treatment with artemether/lumefantrine, providing the first artemisinin-based combination therapies (Coartem) at reduced prices to the WHO. In 2006, after artemisinin had become the treatment of choice for malaria, the WHO called for an immediate halt to single-drug artemisinin preparations in favor of combinations of artemisinin with another malaria drug, to reduce the risk of parasites developing resistance. In 2011, Tu Youyou was awarded the Lasker-DeBakey Clinical Medical Research Award for her role in the discovery and development of artemisinin. On October 5, 2015, she was awarded half of the 2015
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, acco ...
for discovering artemisinin, "a drug that has significantly reduced the mortality rates for patients suffering from malaria". The other half of the prize was awarded jointly to William C. Campbell and
Satoshi Ōmura is a Japanese biochemist. He is known for the discovery and development of hundreds of pharmaceuticals originally occurring in microorganisms. In 2015, he was awarded the Nobel Prize in Physiology or Medicine jointly with William C. Campbell f ...
for discovering
avermectin The avermectins are a group of 16-membered Macrolide, macrocyclic lactone derivatives with potent anthelmintic and Insecticide, insecticidal properties. These naturally occurring compounds are generated as fermentation products by ''Streptomyces a ...
, "the derivatives of which have radically lowered the incidence of
river blindness Onchocerciasis, also known as river blindness, is a disease caused by infection with the parasitic worm ''Onchocerca volvulus''. Symptoms include severe itching, bumps under the skin, and blindness. It is the second-most common cause of blindne ...
and
lymphatic filariasis Lymphatic filariasis is a human disease caused by parasitic worms known as filarial worms. Usually acquired in childhood, it is a leading cause of permanent disability worldwide, impacting over a hundred million people and manifesting itself in ...
, as well as showing efficacy against an expanding number of other parasitic diseases".


Research


New artemisinin-based combination therapies

The WHO notes four additional ACTs that are in preliminary
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s or regionally used for which there is no evidence to recommend widespread use: artesunate/pyronaridine,
arterolane Arterolane, also known as OZ277 or RBx 11160, is an antimalarial compound marketed by Ranbaxy Laboratories. It was discovered by US and European scientists coordinated by the Medicines for Malaria Venture (MMV). Its molecular structure is uncom ...
-
piperaquine Piperaquine is an antiparasitic drug used in combination with dihydroartemisinin to treat malaria. Piperaquine was developed under the Chinese National Malaria Elimination Programme in the 1960s and was adopted throughout China as a replacement ...
, artemisinin-piperaquine base, and artemisinin/naphthoquine.


Helminthiasis

A serendipitous discovery was made in China in the early 1980s while searching for novel
anthelmintic Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them without causing significant damage to the host. They may also ...
s for
schistosomiasis Schistosomiasis, also known as snail fever, bilharzia, and Katayama fever is a neglected tropical helminthiasis, disease caused by parasitism, parasitic Schistosoma, flatworms called schistosomes. It affects both humans and animals. It affects ...
that artemisinin was effective against
schistosomes ''Schistosoma'' is a genus of trematodes, commonly known as blood flukes. They are parasitic flatworms responsible for a highly significant group of infections in humans termed ''schistosomiasis'', which is considered by the World Health Organi ...
, the human blood flukes, which are the second-most prevalent parasitic infections, after malaria. Artemisinin and its derivatives are all potent antihelmintics. Artemisinins were later found to possess a broad spectrum of activity against a wide range of
trematodes Trematoda is a class of flatworms known as trematodes, and commonly as flukes. They are obligate internal parasites with a complex life cycle requiring at least two hosts. The intermediate host, in which asexual reproduction occurs, is a moll ...
, including '' Schistosoma japonicum'', '' S. mansoni'', '' S. haematobium'', ''
Clonorchis sinensis ''Clonorchis sinensis'', the Chinese liver fluke, is a liver fluke belonging to the class trematode, Trematoda, phylum Platyhelminthes. It infects fish-eating mammals, including humans. In humans, it infects the common bile duct and gall bladder, ...
'', ''
Fasciola hepatica ''Fasciola hepatica'', also known as the common liver fluke or sheep liver fluke, is a parasitism, parasitic trematode (fluke (flatworm), fluke or flatworm, a type of helminth) of the class (biology), class Trematoda, phylum Platyhelminthes. It ...
'', and ''
Opisthorchis viverrini ''Opisthorchis viverrini'', common name Southeast Asian liver fluke, is a food-borne trematode parasite from the family Opisthorchiidae that infects the bile duct. People are infected after eating raw or undercooked fish. Infection with the pa ...
''.


Cancer

Artemisinin and its derivatives are under laboratory research for their potential anti-cancer effects. As of 2018, only preliminary clinical research had been conducted using artemisininin derivatives in various cancers, with no approved clinical applications.


Autoimmune disease

Artemisinin derivatives may suppress immune reactions, such as inflammation. One derivative, SM934, was approved in 2015 by the Chinese
National Medical Products Administration The National Medical Products Administration (NMPA; ) is a national bureau responsible for drug supervision under the State Council of China and is managed by the State Administration for Market Regulation. History The agency had multiple fo ...
for a clinical trial as a drug for
systemic lupus erythematosus Lupus, formally called systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Common ...
.


Polycystic ovary syndrome

Artemisinin may be potentially useful for treating symptoms of polycystic ovary syndrome (PCOS).


See also

*
Artemisia (genus) ''Artemisia'' ( ) is a large, diverse genus of plants belonging to the daisy family, Asteraceae, with almost 500 species. Common names for various species in the genus include mugwort, wormwood, and sagebrush. Some botanists split the genus i ...
*
Artemisin Artemisin is a sesquiterpene lactone, similar in structure to α-santonin. See also * Artemisia (genus), hardy herbaceous plants and shrubs known for the powerful chemical constituents in their essential oils * Artemisinin, a group of drugs ...
*
Santonin Santonin is a drug which was widely used in the past as an anthelminthic. It is a terpenoid and an organic compound consisting of colorless flat prisms, turning slightly yellow from the action of light and soluble in alcohol, chloroform and boili ...
*
Pharmacognosy Pharmacognosy is the interdisciplinary scientific study of natural drugs and bioactive compounds from plants, animals, and minerals—originally focused on identifying crude drugs but now expanded to molecular, chemical, ecological, and medicin ...


References


Further reading

* *


External links

* * * {{Xenobiotic-sensing receptor modulators Antimalarial agents Chinese discoveries Experimental cancer drugs Organic peroxides Sesquiterpene lactones Trioxanes Oxygen heterocycles Heterocyclic compounds with 4 rings ATPase inhibitors Traditional Chinese medicine Commercialization of traditional medicines Chinese inventions